Melanoma is a malignant tumor of melanocytes, which are found predominantly in skin but also in the bowel and the eye. It is one of the rarer types of skin cancer but causes the majority of skin cancer related deaths. Malignant melanoma is a potentially serious type of skin cancer. It is due to uncontrolled growth of pigment cells, called melanocytes. Despite many years of intensive laboratory and clinical research, the sole effective cure is surgical resection of the primary tumor before it achieves a thickness greater than 1 mm.
Around 160,000 new cases of melanoma are diagnosed worldwide each year, and it is more frequent in males and caucasians. It is more common in Caucasian populations living in sunny climates than other groups. According to the WHO Report about 48,000 melanoma related deaths occur worldwide per annum. Malignant melanoma accounts for 75 percent of all deaths associated with skin cancer.
The treatment includes surgical removal of the tumor; adjuvant treatment; chemo- and immunotherapy, or radiation therapy.
The risk for developing melanoma depends on two groups of factors: intrinsic and environmental. “Intrinsic” factors are generally an individual's family history and inherited genotype, while the most relevant environmental factor is sun exposure. Epidemiologic studies suggest that exposure to ultraviolet radiation (UVA and UVB) is one of the major contributors to the development of melanoma. UV radiation causes damage to the DNA of cells, typically thymine demonization, which when unrepaired can create mutations. When the cell divides, these mutations are propagated to new generations of cells. If the mutations occur in oncogenes or tumor suppressor genes, the rate of mitosis in the mutation-bearing cells can become uncontrolled, leading to the formation of a tumor. Occasional extreme sun exposure (resulting in “sunburn”) is causally related to melanoma.
Possible significant elements in determining risk include the intensity and duration of sun exposure, the age at which sun exposure occurs, and the degree of skin pigmentation. Exposure during childhood is a more important risk factor than exposure in adulthood. This is seen in migration studies in Australia where people tend to retain the risk profile of their country of birth if they migrate to Australia as an adult. Individuals with blistering or peeling sunburns (especially in the first twenty years of life) have a significantly greater risk for melanoma. This does not mean that sunburn is the cause of melanoma. Instead it is merely statistically correlated. The cause is the exaggerated UV-exposure. It has been shown that sunscreen—while preventing the sunburn—does not protect from melanoma. Many researchers say that sunscreen can even increase the melanoma risk. Fair and red-headed people, persons with multiple atypical nevi or dysplastic nevi and persons born with giant congenital melanocytic nevi are at increased risk.
The incidence of melanoma has increased in the recent years, but it is not clear to what extent changes in behavior, in the environment, or in early detection are involved.
To understand how sunscreen can reduce sunburn and at the same time cause melanoma it is necessary to distinguish between direct DNA damage and indirect DNA damage. Genetic analysis has shown that 92% of all melanoma are caused by the indirect DNA damage. Familial melanoma is genetically heterogeneous, and loci for familial melanoma have been identified on the chromosome arms 1p, 9p and 12q.
The signs and symptoms of melanoma are:                asymmetrical skin lesion.        lesion border is irregular.        melanomas usually have multiple colors.        moles greater than 5 mm are more likely to be melanomas than smaller moles.        
The evolution (i.e. change) of a mole or lesion may be a hint that the lesion is becoming malignant.
The most common types of melanoma in the skin are:                superficial spreading melanoma (SSM)        nodular melanoma        acral lentiginous melanoma        lentigo maligna (melanoma)        
Any of the above types may produce melanin (and be dark in colour) or not (and be amelanotic—not dark). Similarly any subtype may show desmoplasia (dense fibrous reaction with neurotropism) which is a marker of aggressive behaviour and a tendency to local recurrence.
Elsewhere:
clear cell sarcoma (melanoma of soft parts)
mucosal melanoma
uveal melanoma
Features that affect prognosis are tumor thickness in millimeters (Breslow's depth), depth related to skin structures (Clark level), type of melanoma, presence of ulceration, presence of lymphatic/perineural invasion, presence of tumor infiltrating lymphocytes (if present, prognosis is better), location of lesion, presence of satellite lesions, and presence of regional or distant metastasis.
Certain types of melanoma have worse prognoses but this is explained by their thickness. Interestingly, less invasive melanomas even with lymph node metastases carry a better prognosis than deep melanomas without regional metastasis at time of staging. Local recurrences tend to behave similarly to a primary unless they are at the site of a wide local excision (as opposed to a staged excision or punch/shave excision) since these recurrences tend to indicate lymphatic invasion.
When melanomas have spread to the lymph nodes, one of the most important factors is the number of nodes with malignancy. Extent of malignancy within a node is also important; micro metastases in which malignancy is only microscopic have a more favorable prognosis than macro metastases. In some cases micro metastases may only be detected by special staining, and if malignancy is only detectable by a rarely-employed test known as polymerase chain reaction (PCR), the prognosis is better. Macro metastases in which malignancy is clinically apparent (in some cases cancer completely replaces a node) have a far worse prognosis, and if nodes are matted or if there is extra capsular extension, the prognosis is still worse.
When there is distant metastasis, the cancer is generally considered incurable. The five year survival rate is less than 10%. The median survival is 6 to 12 months. Treatment is palliative, focusing on life-extension and quality of life. In some cases, patients may live many months or even years with metastatic melanoma (depending on the aggressiveness of the treatment). Metastases to skin and lungs have a better prognosis. Metastases to brain, bone and liver are associated with a worse prognosis.
Melanoma appears in different stages, which are denoted Stage 0, which is melanoma in situ having 100% survival, Stage I/II, which invasive melanoma having 85-95% survival, Stage II, which is high risk melanoma having 40-85% survival, Stage III which is regional metastasis having 25-60% survival, Stage IV, which is distant metastasis having 9-15% survival based upon AJCC 5-year survival with proper treatment.
Surgery is the first choice therapy for localized cutaneous melanoma. Depending on the stage a sentinel lymph node biopsy is done as well, although controversy exists around trial evidence for this procedure. Treatment of advanced malignant melanoma is performed from a multidisciplinary approach.
High risk melanomas may require adjuvant treatment. In the United States most patients in otherwise good health will begin up to a year of high-dose interferon treatment, which has severe side effects but may improve the patient's prognosis. This claim is not supported by all research at this time, and in Europe interferon is usually not used outside the scope of clinical trials.
Various chemotherapy agents are used, including dacarbazine (also termed DTIC), immunotherapy (with interleukin-2 (IL-2) or interferon (IFN)) as well as local perfusion are used by different centers. They can occasionally show dramatic success, but the overall success in metastatic melanoma is quite limited. IL-2 (Proleukin®) is the first new therapy approved for the treatment of metastatic melanoma in 20 years. Studies have demonstrated that IL-2 offers the possibility of a complete and long-lasting remission in this disease, although only in a small percentage of patients. A number of new agents and novel approaches are under evaluation and show promise.
Radiation therapy is often used after surgical resection for patients with locally or regionally advanced melanoma or for patients with unresectable distant metastases. It may reduce the rate of local recurrence but does not prolong survival.
The molecular background of melanoma progression has been extensively studied and gene expression analysis has identified several genes differentially expressed in invasive forms of melanoma versus less invasive melanoma or benign nevi, one such gene is Wnt-5a (Bittner et al., 2000). Wnt-5a is a secreted, cystein-rich protein that undergoes posttranslational glycosylation and lipid modifications (Kurayoshi et al., 2007). Following its secretion, Wnt-5a acts in an auto- or paracrine fashion by binding to its receptor, in malignant melanoma Wnt-5a has been shown to bind the G-protein coupled receptor Frizzled-5 (Weeraratna, 2002). It is considered as a non-canonical Wnt protein, indicating that it does not primarily act via the β-catenin signaling pathway. The importance of Wnt-5a in cancer progression has been studied in different types of cancer during the last years. Wnt-5a has been shown to have tumour suppressor activity in breast cancer, thyroid cancer, lymphoma, neuroblastoma, colon cancer and liver cancer (Jönsson 2002; Kremenevskaja 2005: Liang 2003; Blanc 2005; Dejmek 2005; Liu 2008). However, in other types of cancer like malignant melanoma and gastric cancer an increased expression of Wnt-5a has been shown to promote tumour progression (Bittner et al., 2000, Weeraratna, 2002; Lewis et al., 2005; Kurayoshi et al., 2006). Based on these results one can conclude that in certain cancers a substance mimicking the effects of Wnt-5a might serve to inhibit tumour progression (Säfholm, 2006) whereas in other cancers, like malignant melanoma, an inhibitor of Wnt-5a-mediated tumour progression would be required.
Regarding the functional downstream effects of Wnt-5a protein in malignant melanoma, only limited knowledge is available (Weeraratna et al., 2002; Dissanayake et al., 2007). In cells derived from melanoma tissue samples an increased expression of the Wnt-5a protein has been shown to induce increased cell adhesion, migration and invasion. In the same study the authors also showed that the effects of Wnt-5a were mediated via the Frizzled-5 receptor and a downstream protein kinase C (PKC) signal (Weeraratna et al., 2002). In a more recent paper, the authors further show that Wnt-5a induces epithelial-mesenchymal transition (EMT) via a PKC-induced expression of Snail that leads to a decrease in the level of E-cadherin but an increase in the level of vimentin (Dissanayake et al., 2007). However, the question still remains as to the actual cause of the increased expression of Wnt-5a in malignant melanomas.
In a recent study by Hoek and co-workers based on DNA microarray analysis it was suggested that transforming growth factor-β (TGF-β) plays a decisive role in the regulation of Wnt-5a gene expression (Hoek et al., 2006). Interestingly enough, members of the TGF-β superfamily (Van Belle et al., 1996) and the bone morphogenic protein (BMP; Rothhammer et al., 2005) exhibit an increased expression in malignant melanoma. Furthermore, at least some functional effects of TGF-β also overlap with that of Wnt-5a. More specifically, as previously mentioned for Wnt-5a, TGF-β1 induces EMT and an increase in melanoma cell migration and metastatic potential (Janji et al., 1999; Gouon et al., 1996. Finally, both Wnt-5a- and TGF-β1 mediate changes in the cellular protein levels of E-cadherin, certain integrins and matrix metalloproteinases (Dissanayake et al., 2007; Janji et al., 1999). There are publications from non-cancer systems that have demonstrated a direct link between TGF-β signaling and Wnt-5a expression. For example, in chick wing bud mesenchymal cells TGF-β3 has been shown to increase Wnt-5a expression resulting in PKCα activation and chondrogenic differentiation (Jin et al., 2006). In a more recent publication in mice, TGF-β1 was shown to increase Wnt-5a expression in mammary epithelial cells leading to inhibition of ductal extension and lateral branching in the developing mammary gland (Roarty and Serra, 2007). Consequently, inhibition of TGF-β signaling could potentially be an attractive mechanism whereby Wnt-5a mediated tumour cell migration and metastasis could be impaired.